OVERALL PROJECT SUMMARY Combusted tobacco use continues to devastate public health in the United States and worldwide. The Tobacco Control Act provides the Food and Drug Administration with the authority to establish product standards for the nicotine content of combusted tobacco products. In this renewal application we address a critical question: What will be the impact of reducing nicotine in cigarettes in the context of alternative tobacco products? If reduced nicotine product standards render combusted tobacco products less reinforcing, smokers who choose not to quit using nicotine/tobacco completely will likely increase their use of non- combusted products. This shift from combusted to non-combusted products could greatly reduce toxicant exposure and reduce the harms associated with tobacco. Three Projects and 3 Cores are proposed. Project 1 (PI: Hatsukami) is a 12-week clinical trial that examines the use of very low nicotine content (VLNC) vs. normal nicotine content (NNC) cigarettes when smokers are provided vouchers to exchange for cigarettes in an experimental marketplace that contains a wide range of non-combusted products. Project 2 (PI: Donny) is a 7- week clinical trial comparing VLNC and NNC cigarettes when participants have access to electronic cigarettes that vary in nicotine concentration (high v. low) and available flavors (tobacco only v. tobacco and other flavors). Project 3 (PIs: Colby & Tidey) is a laboratory-based study that assessed the choice to smoke, vape, or abstain when adolescent smokers are provided cigarettes with VLNC v. NNC and e-cigarettes that vary in nicotine concentrations and flavors. The Cores will provide the infrastructure and resources to conduct these studies. The Administrative Core (Directors: Donny & Hatsukami) will ensure the implementation of appropriate procedures and protocols, the integration of methods, measures, and concepts, the communication and dissemination of information, the generation of new tobacco regulatory science through a pilot project program, and the training of new tobacco regulatory scientists. The Biomarkers Core (Director: Hecht) will provide analysis of biomarkers associated with exposure to nicotine and tobacco-related toxicants. The Biostatistics and Data Management Core (Director: Le) will assist in study design, integration and monitoring of data, data analysis, and, when appropriate, the development of novel ways to analyze data.